Rongcai Liang

Preparation and characterization of puerarin–dendrimer complexes as an ocular drug delivery system

Objective: The aim of this study was to prepare and characterize the complex of puerarin and poly(amidoamine) (PAMAM) dendrimers and to evaluate the complex as an ocular drug delivery system. Methods: The complexes of puerarin and PAMAM dendrimers were prepared at various puerarin-to-dendrimer ratios. The physicochemical properties of the complexes were characterized by differential scanning calorimetry and Fourier transform infrared spectroscopy. The in vitro release studies were performed by dialysis. Corneal permeation was evaluated by Valia-Chien diffusion cell with excised corneas and ocular residence time in rabbits. Results: The results showed that puerarin-dendrimer complexes formed primarily by hydrogen-bonding interactions. Typically, 43, 56, 125, and 170 molecules of puerarin could be incorporated into G3.5, G4, G4.5, and G5 PAMAM dendrimer molecule. Puerarin was released more slowly from puerarin-dendrimer complexes than free puerarin in deionized water and phosphate buffer solution (pH 6.8). The in vitro release rate of puerarin complexed with full generation dendrimers was lower than that with half generation dendrimers. Furthermore, puerarin-dendrimer complexes produced longer ocular residence times in rabbits compared with puerarin eye drops. No damages to the epithelium or endothelium were observed after the PAMAM dendrimer administration in this corneal permeation study. Conclusions: Puerarin-dendrimer complexes represent a potential ocular drug delivery system to improve the efficacy of drug treatment.

Effects of a novel pH-sensitive liposome with cleavable esterase-catalyzed and pH-responsive double smart mPEG lipid derivative on ABC phenomenon

Background The ABC phenomenon is described as a syndrome of accelerated clearance of polyethylene glycol (PEG)-modified liposomes from the bloodstream when repeatedly injected, with their increased accumulation in the liver and spleen. Methods To clarify this immune response phenomenon, we evaluated a novel modified pH-sensitive liposome with a cleavable double smart PEG-lipid derivative (mPEG-Hz-CHEMS). Results The ABC phenomenon in mice was brought about by repeated injection of conventional PEG-PE liposomes and was accompanied by a greatly increased uptake in the liver. However, a slight ABC phenomenon was brought about by repeated injection of mPEG-CHEMS liposomes and was accompanied by only a slightly increased uptake in the liver, and repeated injection of mPEG-Hz-CHEMS liposomes did not induce the ABC phenomenon and there was no increase in liver accumulation. This finding indicates that the cleavable mPEG-Hz-CHEMS derivative could lessen or eliminate the ABC phenomenon induced by repeated injection of PEGylated liposomes. Conclusion This research has shed some light on a solution to the ABC phenomenon using a cleavable PEG-Hz-CHEMS derivative encapsulated in nanoparticles.

pH and temperature dual-sensitive liposome gel based on novel cleavable mPEG-Hz-CHEMS polymeric vaginal delivery system

Background In this study, a pH and temperature dual-sensitive liposome gel based on a novel cleavable hydrazone-based pH-sensitive methoxy polyethylene glycol 2000-hydrazone-cholesteryl hemisuccinate (mPEG-Hz-CHEMS) polymer was used for vaginal administration. Methods The pH-sensitive, cleavable mPEG-Hz-CHEMS was designed as a modified pH-sensitive liposome that would selectively degrade under locally acidic vaginal conditions. The novel pH-sensitive liposome was engineered to form a thermogel at body temperature and to degrade in an acidic environment. Results A dual-sensitive liposome gel with a high encapsulation efficiency of arctigenin was formed and improved the solubility of arctigenin characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. The dual-sensitive liposome gel with a sol-gel transition at body temperature was degraded in a pH-dependent manner, and was stable for a long period of time at neutral and basic pH, but cleavable under acidic conditions (pH 5.0). Arctigenin encapsulated in a dual-sensitive liposome gel was more stable and less toxic than arctigenin loaded into pH-sensitive liposomes. In vitro drug release results indicated that dual-sensitive liposome gels showed constant release of arctigenin over 3 days, but showed sustained release of arctigenin in buffers at pH 7.4 and pH 9.0. Conclusion This research has shed some light on a pH and temperature dual-sensitive liposome gel using a cleavable mPEG-Hz-CHEMS polymer for vaginal delivery.

Improvement of in vivo efficacy of recombinant human erythropoietin by encapsulation in PEG-PLA micelle.

To improve the pharmacokinetics and stability of recombinant human erythropoietin (rhEPO), rhEPO was successfully formulated into poly(ethylene glycol)–poly(d,l-lactide) (PEG–PLA) di-block copolymeric micelles at diameters ranging from 60 to 200 nm with narrow polydispersity indices (PDIs; PDI < 0.3) and trace amount of protein aggregation. The zeta potential of the spherical micelles was in the range of −3.78 to 4.65 mV and the highest encapsulation efficiency of rhEPO in the PEG–PLA micelles was about 80%. In vitro release profiles indicated that the stability of rhEPO in the micelles was improved significantly and only a trace amount of aggregate was found. Pharmacokinetic studies in rats showed highly enhanced plasma retention time of the rhEPO-loaded PEG-PLA micelles in comparison with the native rhEPO group. Increased hemoglobin concentrations were also found in the rat study. Native polyacrylamide gel electrophoresis results demonstrated that rhEPO was successfully encapsulated into the micelles, which was stable in phosphate buffered saline with different pHs and concentrations of NaCl. Therefore, PEG–PLA micelles can be a potential protein drug delivery system.

Novel chitosan derivative for temperature and ultrasound dual-sensitive liposomal microbubble gel.

In this study, a novel liposome-loaded microbubble gel based on N-cholesteryl hemisuccinate-O-sulfate chitosan (NCHOSC) was designed. The structure of the NCHOSC was characterized by FTIR and (1)H NMR. The liposomal microbubble gel based on NCHOSC with a high encapsulation efficiency of curcumin was formed and improved the solubility of curcumin. The diameter of most liposomal microbubble was about 950 nm. The temperature-sensitive CS/GP gel could be formulated at room temperature and would form a gel at body temperature. Simultaneously, the ultrasound-sensitive induced release of curcumin was 85% applying ultrasound. The results of cytotoxicity assay indicated that encapsulated curcumin in Cur-LM or Cur-LM-G was less toxic. The anti-tumor efficacy in vivo suggested that Cur-LM-G by ultrasound suppressed tumor growth most efficiently. These findings have shed some light on the potential NCHOSC material used to liposome-loaded microbubble gel for temperature and ultrasound dual-sensitive drug delivery.

Effect of palmitic acid on the characteristics and release profiles of rotigotine-loaded microspheres

Abstract Background: The initial burst release is a major obstacle to the development of microsphere-formulated drug products. Purpose: To investigate the influence of palmitic acid on the characteristics and release profiles of rotigotine-loaded poly(d,l-lactide-co-glycolide) microspheres. Materials and methods: Rotigotine-loaded microspheres (RMS) were prepared using the oil-in-water emulsion solvent evaporation technique. The in vitro characteristics of the RMS were evaluated with scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and a particle size analyzer. The in vitro drug release and in vivo pharmacokinetics of the RMS were investigated. Results and discussion: The SEM results showed that the addition of palmitic acid changed the surface morphology of the microspheres from smooth to dimpled and then to non-smooth as the palmitic acid content increased. DSC revealed the existence of molecularly dispersed forms of palmitic acid in the microspheres. The in vitro and in vivo release profiles indicated that the addition of 5% and 8% palmitic acid significantly decreased the burst release of rotigotine from the microspheres, and the late-stage release was delayed as the palmitic acid content increased across the investigated range (5–15%). Conclusion: The addition of palmitic acid to the microspheres significantly affects the release profile of rotigotine from RMS.

Preparation and evaluation of rotigotine-loaded implant for the treatment of Parkinson’s disease and its evolution study

Purpose To develop rotigotine-loaded implants (RI) to achieve continuous release of rotigotine for long duration for the treatment of Parkinson’s disease (PD). Methods RI was prepared by hot-melt extrusion method using poly (lactide-co-glycolide) (PLGA) as the matrix. In vitro drug release was optimized by drug loading, melting temperature during preparing process and additives. The surface and internal morphology of RI was imaged by SEM. The in vivo release profile of RI was investigated on rat. Results RI prepared with PLGA 7525 5A showed sustained release of 40 days while suffering a lag phase, which was significantly shortened by blending 5050 2A and mannitol in the matrix. RI prepared by 7525 5A/5050 2A/mannitol = 55:10:5 (rotigotine 30%) showed a 40-day sustained release in vivo with no lag phase. The drug release from RI was also affected by drug loading and melting temperature probably due to the drug state existed in the implant. The evolution of implants during release process was correlated well with the drug release kinetics. Conclusion RI could achieve sustained drug release for 40 days which could supply an alternative of continuous dopaminergic stimulation (CDS) for the treatment of PD.

Application of hot-melt extrusion technology for designing an elementary osmotic pump system combined with solid dispersion for a novel poorly water-soluble antidepressant

Abstract TP1 is a novel antidepressant with poor solubility. To reduce fluctuations in blood concentration and increase oral bioavailability, a controlled-release system was developed by combining a solid dispersion (SD) and an elementary osmotic pump (EOP). The study compared different methods of preparing SDs. Hot-melt extrusion (HME) exhibited clear advantages over the traditional melting technique. An in vitro release study demonstrated that HME-EOP tablets released TP1 in a zero-order manner over 12 h and the drug release was in dependent of the release medium and agitation speed, whereas release from molten-EOP tablets lasted only 8 h. In contrast to immediate-release tablets, the HME-EOP tablets exhibited less fluctuation in blood concentration and higher bioavailability in vivo. In summary, the osmotic pump system combined with an HME-based SD of TP1 presented controlled release in vitro, high bioavailability in vivo and a good in vivo–in vitro correlation.

Synthesis, Characterization and In Vitro Evaluation of Dual pH/Redox Sensitive Marine Laminarin-Based Nanomedicine Carrier Biomaterial for Cancer Therapy

In order to improve the anti-cancer therapy efficiency of hydrophobic drugs such as curcumin (Cur), a novel dual pH/redox sensitive marine laminarin-based nanomedicine carrier biomaterial with photo-dynamic therapy (PDT) was synthesized in this study. The new synthetic chemical structure, named as Hematin-Laminarin-Dithiodipropionic Acid-MGK (HLDM), was characterized by 1H-NMR and IR. The Cur-loaded micelles were then prepared via dialysis method. The HLDM could self-assemble into micelles in water with hydrodynamic diameter of 135±15 nm. The particle size, zeta potential and morphology of micelles were detected by transmission electron microscope (TEM). Interestingly, the in vitro release experiment showed that the release amount of Cur-loaded HLDM micelles could reach 80% in the pH and redox sensitive environment. Furthermore, cell study showed that the Cur-loaded HLDM micelles had stronger cellular uptake and cytotoxicity to MCF-7 cells than that of HLDM. The multifunctional marine laminarin based nanomedicine carrier biomaterial can be used for new drug delivery systems with dual pH/redox sensitivity for cancer therapy.